Clostridium difficile is a Gram-positive, spore-forming anaerobic and toxin-producing bacillus. It is the most common cause of nosocomial antibiotic-associated diarrhea and the etiologic agent of pseudomembranous co- litis with about 453,000 cases and 29,000 deaths yearly in the U.S. as reported by CDC in 2015. Central to predisposition to C. difficile infection (CDI) is the disruption of the gut microbiota by antibiotics. The first-line therapy for the treatment of CDI is oral metronidazole or vancomycin. None of these is fully effective, and an estimated 15-35% of those infected with C. difficile relapse following treatment. The recently approved fidax- omicin has improved efficacy in preventing recurrence, but its high cost precludes its routine use. As such, novel antibiotic agents with low cost and high efficacy are desperately needed to address the alarming CDI epidemic. We recently have developed a new series of biodegradable polymer biomaterials-polycarbonates. These pol- ymers, containing both hydrophobic and cationic groups, mimic host-defense peptides (HDPs) and kill bacteria through disruption of bacterial membranes. Importantly, these polymers can be orally administered and eradicate C. difficile infection in mice with high efficacy which is even superior to vancomycin. Furthermore, these polymers are not active against Gram-negative bacteria, and therefore they do not destroy commensal Gram-negative intestinal microbes such as E. coli. To the best of our knowledge, this is the first example of biodegradable polymers with oral bioavailability against C. difficile to date. Compared to vancomycin, these polymers are easy to synthesize in a large scale with very low cost, and highly amendable to optimization, making them very prom- ising for antibiotic therapy against C. difficile. Our long-term goal is to develop biodegradable polycarbonates as new generation of antibiotics against C. difficile. The objective of this project is to further develop these biode- gradable polymers with greater potency through optimization. As such, based on our preliminary results, we will first design and synthesize new generation of polycarbonate derivatives bearing optimized hydrophobic and cationic groups that can kill C. difficile with higher potency and selectivity. Following that, we will determine antibacterial activity and selectivity of the newly designed polymers against C. difficile. The most potent polymers (MIC < 0.5 g/mL, Selective Index (SI): HC50/MICC.difficile > 2000 for blood cells, IC50/MICC.difficile > 250 for mamma- lian cells) will be further explored for their mechanism of action. Subsequently, we will also evaluate therapeutic efficacy of these most potent polycarbonates in animal models (mouse model and acute hamster model) of CDI. Our project is significant, because we are tackling the infection from the significant bacterial strain C. difficile, and we are developing novel polymeric biomaterials. We also believe our project is innovative, as we are de- veloping a new class of biodegradable and orally available polycarbonates, which have already showed remark- able efficacy and selectivity, and could be synthesized in large scale with low cost. As a result, a new generation of antibiotic agents combating C. difficile will be resulted from our project.